Pd‐Catalyzed Stereospecific Azide Substitution of α,β‐Unsaturated γ,δ‐Epoxy Esters with Double Inversion of Configuration

Abstract

Over recent years, much interest has been focused on the development of not only a stereoselective but also a practical methodology for the synthesis of chiral b-amino alcohols, [1] aamino acids, [2] and a,a-disubstituted amino acids [2][3][4] (including natural and unnatural congeners) in the context of medicinal chemistry. Although many synthetic approaches to these biologically important compounds have been reported, [1][2][3][4] there is still a need for a new type of methodology that allows the stereospecific synthesis of functionalized amino alcohols and amino acids that bear contiguous chiral centers. We report herein an approach that permits the highly stereoselective synthesis of a variety of amino alcohols, amino acids, and quaternary amino acids, including acyclic and cyclic congeners. This methodology involves the palladium-catalyzed stereospecific azide substitution reaction of a,b-unsaturated g,d-epoxy esters with a double inversion of configuration as the key step.In connection with our recent studies on the palladiumcatalyzed stereospecific hydroxy substitution reactions of unsaturated g,d-epoxy esters with phenylboronic acid [5] and boric acid [6] with a double inversion of configuration, we anticipated that the palladium-catalyzed azide substitution reaction of a,b-unsaturated g,d-epoxy esters with an appropriate azide reagent might occur by a similar p-allyl palladium species to afford an azide substitution product with double inversion of configuration, as shown in Scheme 1. Namely, this new method involves two consecutive S N 2 processes to afford a substitution product with double inversion of configuration in contrast with the normal S N 2 epoxideopening reactions. [7] Initially, we chose ethyl trans-4,5-epoxy-(2E)-octenoate (1) [5] as a model substrate and examined its palladiumcatalyzed reaction with TMSN 3 to confirm whether such a reaction indeed takes place. Thus, first TMSN 3 (2 equiv) then a palladium catalyst ([Pd(PPh 3 ) 4 ] (10 mol %)) was added to a solution of 1 in THF and the mixture was stirred at room temperature for 20 minutes. The reaction was then quenched with a solution of citric acid in MeOH. The azide substitution reaction of 1 with double inversion of configuration did occur at the g-position to afford a single syn azido alcohol 2 in 90 % yield of the isolated product after purification by chromatography on silica gel (Scheme 2). The configuration of the product was unambiguously determined by NOE interaction studies of its d-lactone derivative 3, which was readily derived from 2 by catalytic hydrogenation in the presence of di-tertbutyl dicarbonate (Boc 2 O) [8] followed by lactonization with PPTS in dichloroethane (Scheme 2). It should be noted that the present palladium-catalyzed azide substitution reaction took place not only in high yield but also with complete stereoselectivity, thus giving rise to the single product with a double inversion of configuration.

Palladium‐Catalyzed Stereospecific Substitution of α,β‐Unsaturated γ,δ‐Epoxy Esters by Alcohols with Double Inversion of Configuration: Synthesis of 4‐Alkoxy‐5‐hydroxy‐2‐pentenoates

“…Although a variety of regio‐ and stereoselective substitution reactions of epoxides by an S N 2 mechanism have so far been reported,1 the stereospecific substitution reaction which proceeds with double inversion of configuration, that is, retention of configuration, is only limited 2. 3 As part of a program to develop such types of reactions, we recently reported the palladium‐catalyzed stereospecific azide substitution reaction of α,β‐unsaturated γ,δ‐epoxy esters with trimethylsilylazide with double inversion of configuration 4. We have also developed palladium‐catalyzed stereospecific hydroxy substitution reactions of α,β‐unsaturated γ,δ‐epoxy esters with alkylboronic acid5 and with boric acid6 to give cyclic alkyl boronates and γ,δ‐vicinal diol derivatives, respectively, with double inversion of configuration 7.…”

Palladium‐Catalyzed Stereospecific Substitution of α,β‐Unsaturated γ,δ‐Epoxy Esters by Alcohols with Double Inversion of Configuration: Synthesis of 4‐Alkoxy‐5‐hydroxy‐2‐pentenoates

“…[2,3] As part of a program to develop such types of reactions, we recently reported the palladium-catalyzed stereospecific azide substitution reaction of a,b-unsaturated g,d-epoxy esters with trimethylsilylazide with double inversion of configuration. [4] We have also developed palladiumcatalyzed stereospecific hydroxy substitution reactions of a,bunsaturated g,d-epoxy esters with alkylboronic acid [5] and with boric acid [6] to give cyclic alkyl boronates and g,d-vicinal diol derivatives, respectively, with double inversion of configuration. [7] From mechanistic analyses of these reactions and the precedent report by Trost et al, [8] we anticipated that the palladium-catalyzed stereospecific substitution reaction of an a,b-unsaturated g,d-epoxy ester with an alcohol nucleophile might occur in the presence of an appropriate boron reagent to afford a g-alkoxy substitution product with double inversion of configuration (Scheme 1).…”

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